LONG-ACTING NIFEDIPINE PREPARATION

Description

[0001] The present invention relates to a novel preparation of nifedipine, more particularly, to an easily absorbable, sustained-release preparation of nifedipine.

[0002] Nifedipine has excellent coronary vasodilating and hypotensive activities, but on the other hand, it has such drawbacks that it is hardly soluble in water and has less absorbability in body liquids, and further that it is rapidly metabolized and excreted.

[0003] Nifedipine has now been widely used as a medicine for the treatment of angina pectoris, and since the attack of angina pectoris suddenly occurs, it is required to be administered immediately when the patient is attacked by the disease and further the drug should exhibit its activity rapidly after administration. From this viewpoint, it has been proposed to prepare easily absorbable (rapid-action) preparations of nifedipine. For instance, a preparation is made by dissolving nifedipine in liquid polyethylene glycol and packing the solution in a soft capsule (cf. Japanese Patent First Publication No. 28621/1973), and nifedipine is formed in a solid solution preparation (cf. Kiso-to-Rinsho, Vol. 18, page 1648, 1979).

[0004] These easily absorbable preparations are in fact useful for the treatment of angina pectoris, because nifedipine is easily absorbed within the body and the blood level of nifedipine becomes rapidly high level. However, in such easily absorbable preparations, nifedipine is undesirably rapidly metabolized and excreted, and hence, the blood level is rapidly lowered.

[0005] Nifedipine is useful not only for the treatment of angina pectoris, but also for the prophylaxis of angina pectoris and further for the treatment of hypertension. For the latter purpose, it is required that an effective blood level of nifedipine is maintained for a long period of time in addition to the easy absorption thereof.

[0006] EP-A-0 047 899 discloses solid nifedipine preparations comprising nifedipine crystals with a specific surface in the range of 0.5 to 6 m²/g. The use of crystals with the above specific surface results in a rapid absorption and a long period of efficiency of the ingredient nifedipine.

[0007] An object of the present invention is to provide a nifedipine preparation which shows good absorbability of nifedipine and can maintain the therapeutically effective blood level of nifedipine for a long period of time by one time administration, i.e. a nifedipine preparation having both easy absorbability and sustained-release.

[0008] Another object of the present invention is to provide a nifedipine preparation suitable for the prophylaxis and treatment of angina pectoris and hypertension.

[0009] That is, the present invention relates to a sustained-release nifedipine preparation which comprises the following Compositions (A) and (B) in a ratio of 15:85―50:50 by weight of nifedipine,

[0010] Composition (A): a rapid-release preparation containing as an active ingredient nifedipine crystalline fine powder having an average particle size of not more than 5 µm in admixture with a pharmaceutically acceptable carrier,

[0011] Composition (B): a delayed-release preparation containing as the active ingredient nifedipine fine powder having an average particle size of not more than 5 µm and having a surface coating layer comprising a non-toxic hardly water-soluble substance selected from ethyl cellulose, hydrogenated oil and glycerin fatty acid ester, and an enteric high molecular compound selected from cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate and methacrylic acid methyl methacrylate copolymer in a weight ratio of 1:5 to 5:1.

[0012] The rapid-release preparation means the above nifedipine fine powder per se or a conventional preparation made by subjecting a mixture of said fine powder with a conventional pharmaceutically acceptable carrier to granulation or fine granulation procedure. The delayed-release preparation is prepared by applying a specific release-sustaining means to the same preparation as the above rapid-release preparation. The effectiveness and characteristics of the present composition comprising such Composition (A) and Composition (B) are made clear from the comparison of blood level of nifedipine in case of administration of Preparation a of the present invention (Example 1), a conventional solid solution preparation (Reference Preparation i) and a conventional fine powder granulation preparation of nifedipine (Reference Preparation ii) (cf. Experiment 1, Fig. 1).

[0013] Thus Fig. 1 shows change of blood level of nifedipine after orally administering the above three kinds of preparations containing each 20 mg of nifedipine to Beagle dogs. As is clear from the results, the solid solution preparation (Reference Preparation _/1 and fine powder granulation preparation (Reference Preparation iij showed rapid increase of the blood level when administered, and the blood level became very high, but it lowered rapidly. Such an initial high level is unfavorable in view of side effects, and further, such a rapid lowering of the blood level is not suitable in view of release sustaining.

[0014] On the contrary, Preparation a of the present invention showed a very plane pattern in the blood level curve, i.e. the blood level of nifedipine was maintained in the range of 40 to 60 ng/ml from 1 to 9 hours after the administration (totally for 8 hours), and further, at the first stage after administration, the blood level satisfactorily increased. Thus, it is clear that this preparation is suitable as a sustained-release preparation.

[0015] The preparation of the present invention and method for preparing the same are explained in more detail below.

[0016] Firstly, in the preparation of the present invention, it is characteristic to employ as the active ingredient nifedipine fine powder having an average particle size of not more than 5 pm, preferably 1 to 4 pm.

[0017] Such a nifedipine fine powder can be obtained by pulverizing the conventional crystalline nifedipine (average particle size thereof is usually more than 30 µm) by conventional methods using ball-mill, jet-mill, or automated mortar, optionally followed by subjecting to screening.

[0018] In addition to the application of specific release-sustaining means disclosed hereinafter, the above feature of average particle size of not more than 5 µm is important for satisfying two requirements of the easy absorption of the medicament and the maintaining the high blood level of the medicament.

[0019] That is, as is clear from Fig. 2 which shows change of blood level of nifedipine after administering to Beagle dogs the preparations made from nifedipine fine powders having an average particle size of 2.1 µm, 5.0 µm and 9.6 µm [Preparation a of the present invention, Preparation b of the present invention, and Reference Preparation iii (cf. Experiment 2), respectively], Preparation a (nifedipine average particle size: 2.1 µm) and Preparation b (said size: 5.0 pm) of the present invention showed a blood nifedipine level of more than 40 ng/ml one hour after the administration and could maintain the blood level at the range of about 40 to 60 ng/ml for 8 to hours after the administration, but on the contrary, Reference Preparation iii (said size: 9.6 tim) required about 3 hours after administration for increasing the blood nifedipine level to 40 ng/ml, and the level lowered to less than 40 ng/ml after about 7 hours. Thus, it is inferior in both the absorbability and the release sustaining properties.

[0020] In the preparation of a sustained-release preparation of nifedipine, an easily absorbable nifedipine solid solution may be. used as the active ingredient after making a part thereof in the sustained-release form, but according to the present inventors' study, when the solid solution is made in the sustained-release form, it is wetted within the peptic tract when administered, which results in crystallization of nifedipine and then to lowering of absorption, and hence, it can hardly maintain the desired blood nifedipine level for a long period of time. Thus, it has first been found that the practically useful sustained-release nifedipine preparation can be prepared by using a nifedipine fine powder having an average particle size of not more than 5 pm.

[0021] Another characteristic of the present preparation is that the rapid-release preparation (Composition A) is prepared by using the above nifedipine fine powder and separately the delayed-release preparation (Composition B) is prepared by subjecting the rapid-release preparation to the specific release sustaining means as mentioned hereinafter, and then both compositions are incorporated in a fixed ratio.

[0022] As defined above, Composition (A) is the nifedipine fine powder per se, or a preparation obtained by admixing the fine powder with pharmaceutically acceptable carriers such as excipients, filling agents, binding agents, etc., followed by subjecting the mixture to the conventional granulation or fine granulation procedure. This Composition (A) can rapidly release the easily absorbable nifedipine fine powder when administered and can give early increase of the blood nifedipine level.

[0023] On the other hand, Composition (B) is obtained by firstly preparing a granule or fine granule of the nifedipine fine powder like in the above Composition (A) and then coating the granule with a coating layer comprising a pharmaceutically acceptable, hardly water-soluble substance selected from ethyl cellulose, hydrogenated oil and glycerin fatty acid ester (hereinafter, referred to merely as "hardly soluble substance) and an enteric high molecular compound selected from cellulose acetate phthalate hydroxypropylmethyl cellulose phthalate and methacrylic acid methyl methacrylate copolymer. It is one of the important characteristics of the present invention to use as the coating layer a mixture of the hardly soluble substance and the enteric high molecular compound, by which the desired slow- and sustained-release of nifedipine is effected and then the fixed blood nifedipine level can be maintained for a long period of time. Instead of the above, when the hardly soluble substance or the enteric high molecular compound is used alone for the coating, and when such a coated preparation thus obtained is combined with Composition (A), the former case (Reference Preparation iv) shows too slow a release of nifedipine and hence the utilizing ratio of nifedipine is decreased, and on the other hand, in the latter case (Reference Preparation v) shows too rapid a release of nifedipine and hence the blood nifedipine level is rapidly lowered. Thus, both preparations can not exhibit the desired effects as in the preparation of the present invention (Preparation a) (cf. Experiment 3, Fig. 3). Representative examples of the hardly soluble substance used in Composition (B) are ethyl cellulose, hydrogenated oils as defined in Japan Pharmacopeia, 10th Edition, or glycerin fatty acid esters as defined in Foodstuff Additives Regulation, 4th Edition. The hydrogenated oils include, for example, hydrogenated products of fish oil, whale oil or soybean oil. The glycerin fatty acid esters include anyone of mono-, di- or tri-ester. These hardly soluble substances may be used in combination of two or more thereof.

[0024] The enteric high molecular compounds may also be used in combination of two or more thereof.

[0025] The above hardly soluble substances and enteric high molecular compounds can be combined in various ways. Preferred combinations are, for example, a combination of a hydrogenated oil and hydroxypropylmethyl cellulose phthalate, a combination of a hydrogenated oil and methacrylic acid-methyl methacrylate copolymer, a combination of glycerin monostearate and hydroxypropylmethyl cellulose phthalate, or the like. The hardly soluble substances and the enteric high molecular compounds are mixed in the weight ratio of 1:5 to 5:1, particularly 1:2 to 2:1 of the hardly soluble substance:the enteric high molecular compound.

[0026] The coating is carried out by dissolving the above hardly soluble substance and enteric high molecular compound in a common solvent (e.g. ethanol, dichloromethane, etc.) and then coating the solution onto the granules or fine granules obtained above by a conventional coating method, such as pan coating, fluidized bed coating, or the like.

[0027] The coating amount varies depending on the components of the coating layer, shape and particle size of the substance to be coated and is not specified, but is usually in the range of 7 to 100% by weight (calculated in the increase ratio of the solid components).

[0028] The preparation of the present invention is made from the above-prepared Composition (A) and Composition (B). In the preparation, Composition (A) and Composition (B) are incorporated in the ratio of 15:85 to 50:50, preferably 20:80 to 40:60, by weight of nifedipine. When the mixing ratio of both compositions is outside the above-mentioned ratio, the initial blood level is not sufficiently raised and/or the blood level is not sufficiently maintained, and hence, the desired sustained-release preparation can not be obtained (cf. Experiment 4, Fig. 4).

[0029] The preparation of the present invention is preferably in the non-compressed form, and particularly preferably, both Composition (A) and Composition (B) are prepared in the form of a granule or fine granule and are simply mixed, or the granular or fine granular compositions are packed in capsules to obtain a capsule preparation. Besides, both Compositions (A) and (B) may be simultaneously administered without previously making in one-pack preparation. Such an embodiment is also included within the present invention.

[0030] The usage and dosage of the preparation of the present invention may vary according to the object for use or the subject to be administered, but in case of Preparation a of the present invention as disclosed in Example 1 hereinafter, it can for example maintain the minimum effective blood level of nifedipine at 30 ng/ ml for about 9 hours after only one administration of one capsule (cf. Experiment 5, Fig. 5). Accordingly, this may be used as an index for determining the effective usage and dosage.

[0031] That is, in case of Preparation a of the present invention (a capsule containing 20 mg of nifedipine), it is usually administered in a dose of one capsule per each time at an interval of 8 to 12 hours for the prophylaxis and treatment of angina pectoris and hypertension.

[0032] The present invention is illustrated by the following Examples and Experiments in more detail.

Example 1

Capsules

(1) Preparation of Composition (A):

[0033] [A-1]: To a mixture of nifedipine fine powder having an average particle size of 2.1 µm (200 g), lactose (150 g), corn starch (80 g), crystalline cellulose (250 g) and carboxymethyl cellulose calcium (300 g) is added an aqueous solution of hydroxypropyl cellulose (20 g), and the mixture is well kneaded. The mixture is granulated with a cylindrical granulating machine and then is formed in a round shape with a Marumerizer, and dried at 50°C for 12 hours to give granules containing nifedipine of 20 mg/100 mg (particle size: 12-32 mesh).

[0034] [A-2]: In the same manner as described in the above [A-1 ] except that nifedipine fine powder having an average particle size of 5.0 µm is used, there are prepared granules containing nifedipine of 20 mg/ 100 mg (particle size: 12-32 mesh).

(2) Preparation of Composition (B):

[0035] [B-1]: Composition [A-1] (500 g) obtained above is entered in a coating pan and is subjected to spray coating using a coating liquid consisting of hydroxypropyl methyl cellulose phthalate (tradename, HP-55, manufactured by Shinetsu Kagaku K.K.) (400 g), glycerin monostearate (400 g), triacetine (70 g), ethanol (4,500 g) and dichloromethane (4,630 g) until the weight of granules becomes 880 g to give coated granules.

[0036] [B-2]: In the same manner as described above [B­1 ] except that Composition [A-2] (500 g) is used instead of Composition [A­1] (500 g), there are prepared coated granules.

[0037] [B-3]: In the same manner as described above [B-1] except that the coating liquid contains a hydrogenated oil (Japan Pharmacopeia 10 Edition) (300 g) instead of glycerin monostearate (400 g), there are prepared coated granules.

(3) Preparation of capsules (a preparation of the present invention):

[0038] Composition (A) and Composition (B) obtained above are mixed in the ratios as shown in Table 1, and each mixture is packed into 3# hard capsules to give 5 kinds of capsules wherein nifedipine is contained in an amount of 20 mg per each capsule (Preparation a, b, c, d and e of the present invention).

Example 2

Granules

(1) Preparation of Composition (A):

[0039] To a mixture of nifedipine fine powder having an average particle size of 2.2 µm (10 g), lactose (200 g) and corn starch (180 g) is added an aqueous solution of hydroxypropyl cellulose (10 g), and the mixture is kneaded and granulated, dried at 60°C for one hour and then subjected to screening to give granules (particle size: 14-24 mesh).

(2) Preparation of Composition (B):

[0040] In the same manner as described above (1), there are prepared granules (particle size: 14-24 mesh) by using nifedipine fine powder having an average particle size of 2.2 pm (20 g), lactose (500 g), corn starch (450 g) and hydroxypropyl cellulose (30 g). The granules (500 g) thus prepared are entered into a coating pan and subjected to spray coating using a coating liquid consisting of methacrylic acid-methyl methacrylate copolymer (tradename, Eudragit® L, manufactured by Rohm Pharm.) (50 g), glycerin monostearate (40 g), and ethanol (1,000 g) until the weight of granules becomes 800 g to give coated granules.

(3) Preparation of granules (a preparation of the present invention):

[0041] Composition (A) (200 g) and Composition B (800 g) prepared above are well mixed, and the mixture (each 1 g) is folded in a powder paper to give folded granules wherein each granule contains 5 mg of the rapid-release nifedipine and 10 mg of delayed-release nifedipine (totally 15 mg).

Example 3

Granules

[0042] In the same manner as described in Example 2 except that the coating liquid in Example 2-(2) [Preparation of Composition (B)] contains ethyl cellulose (50 g) instead of glycerin monostearate (40 g), there are prepared folded granules wherein each granule contains 5 mg of the rapid-release nifedipine and 10 mg of delayed-release nifedipine.

Experiments 1-4

Bood nifedipine level when administered to Beagle dogs:

[0043] 

As to the preparations prepared in the above Examples 1 to 3, the change of blood nifedipine level with lapse of time was studied by administering them to Beagle dogs.

[0044] Test method: The test preparation (20 mg as nifedipine) was orally administered to Beagle dogs (weighing 8-11 kg, one group: 5 dogs). After bleeding at an interval, the blood nifedipine level was measured by ECD gas chromatography. The results are shown in the average of the data obtained in five dogs.

Experiment 1

Comparison between the preparation of the present invention and the easily absorbable solid solution

preparation and easily absorbable fine powderpreparation:

[0045] 

A. Preparations to be tested

(1) Preparation a of the present invention prepared in Example 1

(2) Easily absorbable solid solution preparation (Reference Preparation i)

[0046] It is a granule preparation (containing nifedipine of 20 mg per 1 g) which is prepared by entering fine granulated sugar (920 g) into a spray granulating machine and then spray coating it with a solution of nifedipine (20 g) and polyvinylpyrrolidone (average molecular weight: 40,000) (60 g) in dichloromethane.

[0047] 

(3) Easily absorbable fine powder preparation (Reference Preparation ii1

It is Composition [A-1] prepared in Example 1

B. Results of the experiment

[0048] The change of the blood nifedipine level with lapse of time after each preparation was administered is shown in the accompanying Fig. 1.

[0049] Besides, when the granule preparations as prepared in Example 2 and Example 3 were administered to Beagle dogs, they showed almost similar change of the blood nifedipine level to that of Preparation a of the present invention as shown in Fig. 1, and in both cases, the blood level of 40 to 60 ng/ml was maintained for about 8 hours from one hour after the administration.

Experiment 2

Average particle size of nifedipine and change of blood nifedipine level:

[0050] 

A. Compositions to be tested

(1) Preparation a of the present invention prepared in Example 1 (using nifedipine having an average particle size of 2.1 pm)

(2) Preparation b of the present invention prepared in Example 1 (using nifedipine having an average particle size of 5.0 pm)

(3) Reference Preparation iii (using nifedipine having an average particle size of 9.6 µm) as mentioned below

[0051] In the same manner as in the preparation of Preparation a of the present invention as described in Example 1 except that nifedipine fine powder having an average particle size of 9.6 pm, there were prepared capsules (each capsule containing 20 mg of nifedipine).

B. Results of the experiment

[0052] The change of the blood nifedipine level when the above three preparations were administered is shown in the accompanying Fig. 2.

Experiment 3

Components of the coating layer and the change of the blood nifedipine level

[0053] A. Compositions to be tested

(1) Preparation a of the present invention prepared in Example 1 (using together a hardly soluble substance and an enteric high molecular compound)

(2) Reference Preparation iv (using a hardly soluble substance alone) as mentioned below

[0054] The same Composition [A-1] as in Example 1 and a delayed-release Composition [B'-1] prepared as described below were mixed in a ratio of 30:70 (w/w) (as.the weight of nifedipine), and the mixture was packed in 3# hard capsule to give capsules (each capsule containing 20 mg of nifedipine).

[0055] Preparation of a delayed-release Composition [B'-1]:

[0056] It was prepared in the same manner as in the preparation of the Composition [B-1] as described in Example 1 except that the coating liquid contains glycerin monostearate (500 g) alone instead of hydroxypropyl methyl cellulose phthalate (400 g) and glycerin monostearate (400 g).

[0057] (3) Reference Preparation v (using an enteric high molecular compound alone) as mentioned below

[0058] The same Composition [A-1] as in Example 1 and a delayed-release Composition [B'-2] prepared as described below were mixed in a ratio of 30:70 (w/w) (as the weight of nifedipine), and the mixture was packed in 3# hard capsules (each capsule containing 20 mg of nifedipine).

[0059] Preparation of a delayed-release Composition [B'-2]:

[0060] It was prepared in the same manner as in the preparation of the Composition [B-1] as described in Example 1 except that the coating liquid contains hydroxypropyl methyl cellulose phthalate (500 g) alone instead of hydroxypropyl methyl cellulose phthalate (400 g) and glycerin monostearate (400 g).

B. Results of the experiment

[0061] The change of the blood nifedipine level with lapse of time after each preparation was administration is shown in the accompanying Fig. 3.

Experiment 4

Mixed ratio of Composition (A) and Composition (B) and the change of the blood nifedipine level

[0062] A. Compositions to be tested

[0063] (1) Reference Preparation vi [rapid-release nifedipine:delayed release nifedipine = 10:90 (w/w)] as prepared below

[0064] Composition [A-1] and Composition [B-3] as prepared in Example 1 were mixed in a ratio of 10:90 (w/w) (calculated as the weight of nifedipine), and the mixture was packed in 3# hard capsule to give capsules (each one capsule containing 20 mg of nifedipine).

[0065] 

(2) Preparation c of the present invention as prepared in Example 1 [rapid-release nifedipine:delayed-release nifedipine = 15:85 (w/w)]

(3) Preparation d of the present invention as prepared in Example 1 [rapid-release nifedipine:delayed-release nifedipine = 30:70 (w/w)]

(4) Preparation e of the present invention as prepared in Example 1 [rapid-release nifedipine:delayed-release nifedipine = 50:50 (w/w)]

(5) Reference Preparation vii [rapid-release nifedipine:delayed-release nifedipine = 60:40 (w/w)] as prepared below

[0066] Composition [A-1] and Composition [B―3] as prepared in Example 1 were mixed in a ratio of 60:40 (w/w) (calculated as the weight of nifedipine), and the mixture was packed in 3# hard capsule to give capsules (each one capsule containing 20 mg of nifedipine).

B. Results of the experiment

[0067] The change of the blood nifedipine level with lapse of time after each preparation was administered is shown in the accompanying Fig. 4.

Experiment 5

Blood nifedipine level when administered to human:

[0068] 

In order to make clear effectiveness of the preparation of the present invention when administered to humans, Preparation a of the present invention and Reference Preparation i were administered to humans and change of the blood nifedipine level was measured.

A. Test method

[0069] Preparation a of the present invention (20 mg, calculated as nifedipine) and Reference Preparation i (10 mg, calculated as nifedipine) were each administered to healthy male adults (4 men), and after the administration, blood was collected at an interval with the lapse of time, and the blood nifedipine level was measured by ECD gas chromatography. The results are shown in average of four test persons.

B. Results of the test

[0070] The results are shown in Fig. 5. According to the results shown in Fig. 5, when Preparation a of the present invention was administered, the blood nifedipine level was 30 ng/mi which is the minimum effective blood level in humans or higher than it, and the blood level was maintained from one hour to 10 hour after the administration, i.e. for about 9 hours. It is clear from this that the preparation of the present invention is useful as a sustained-release nifedipine preparation.

Claims

1. A sustained-release nifedipine preparation which comprises the following Composition (A) and Composition (B) in a ratio of 15:85 to 50:50 by weight of nifedipine,

Composition (A): a rapid-release preparation containing as an active ingredient nifedipine crystalline fine powder having an average particle size of not more than 5 µm in admixture with a pharmaceutically acceptable carrier,

Composition (B): a delayed-release preparation containing as the active ingredient nifedipine fine powder having an average particle size of not more than 5 pm and having a surface coating layer comprising a non-toxic hardly water-soluble substance selected from ethyl cellulose, hydrogenated oil and glycerin fatty acid ester, and an enteric high molecular compound selected from cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate and methacrylic acid methyl methacrylic copolymer in a weight ratio of 1:5 to 5:1.

2. The sustained-release nifedipine preparation according to claim 1, wherein Composition (A) and Composition (B) are mixed in a ratio of 20:80 to 40:60 by weight of nifedipine, and the hardly water-soluble substance and the enteric high molecular compound are used in a ratio of 1:2 to 2:1 (weight ratio).

3. The sustained-release nifedipine preparation according to claim 1 or 2, wherein the nifedipine fine powder has an average particle size of 1 to 4 um.

4. The sustained-release nifedipine preparation according to claim 1 or 2, wherein the nifedipine fine powder has an average particle size of about 2 µm.

5. The sustained-release nifedipine preparation according to claim 1, wherein the preparation is in the form of a non-compressed type.

6. The sustained-release nifedipine preparation according to claim 5, wherein the preparation form is a granule or fine granule preparation which is prepared by mixing a granular or fine granular Composition (A) and a granular or fine granular Composition (B), or a capsule preparation which is prepared by packing said granule or fine granule preparation into a capsule.

Ansprüche

1. Nifedipin-Zubereitung mit Langzeitwirkung, die die folgenden Zusammensetzungen (A) und (B) in einem Verhältnis von 15:85 bis 50:50 in Bezug auf das Gewicht von Nifedipin umfaßt,

Zusammensetzung (A): Zubereitung mit schneller Freisetzung, die als einen Wirkstoff ein kristallines, feines Nifedipinpulver mit einer durchschnittlichen Teilchengröße von nicht mehr als 5 µm in Mischung mit einem pharmazeutisch verträglichen Träger enthält,

Zusammensetzung (B): eine Zubereitung mit verzögerter Freisetzung, die als Wirkstoff feines Nifedipinpulver mit einer durchschnittlichen Teilchengröße von nicht mehr als 5 µm und mit einer Oberflächenüberzugsschicht, die eine nicht toxische, kaum wasserlösliche Substanz, ausgewählt aus Ethylzellulose, hydriertem Öl und Glycerinfettsäureester, und eine enterische, hochmolekulare Verbindung, ausgewählt aus Zelluloseacetatphthalat, Hydroxypropylmethylzellulosephthalat und Methacrylsäure/ Methylmethacrylat-Copolymer, in einem Gewichtsverhältnis von 1:5 bis 5:1 umfaßt, enthält.

2. Nifedipin-Zubereitung mit Langzeitwirkung nach Anspruch 1, wobei die Zusammensetzung (A) und die Zusammensetzung (B) in einem Verhältnis von 20:80 bis 40:60 in Bezug auf das Gewicht von Nifedipin vermengt sind, und die kaum wasserlösliche Substanz und die enterische, hochmolekulare Verbindung in einem Verhältnis von 1:2 bis 2:1 (Gewichtsverhältnis) verwendet sind.

3. Nifedipin-Zubereitung mit Langzeitwirkung nach Anspruch 1 oder 2, wobei das feine Nifedipinpulver eine durchschnittliche Teilchengröße von 1 bis 4 um besitzt.

4. Nifedipin-Zubereitung mit Langzeitwirkung nach Anspruch 1 oder 2, wobei das feine Nifedipinpulver eine durchschnittliche Teilchengröße von ungefähr 2 um aufweist.

5. Nifedipin-Zubereitung mit Langzeitwirkung nach Anspruch 1, wobei die Zubereitung in Form einer nichtgepreßten Art vorliegt.

6. Nifedipin-Zubereitung mit Langzeitwirkung nach Anspruch 5, wobei die Zubereitungsform eine körnige oder feinkörnige Zubereitung ist, die durch Mischen einer körnigen oder feinkörnigen Zusammensetzung (A) und einer körnigen oder feinkörnigen Zusammensetzung (B) hergestellt ist, oder eine Kapselzubereitung ist, die hergestellt wird, indem man die körnige oder feinkörnige Zubereitung in eine Kapsel packt.

Revendications

1. Une préparation de nifédipine à libération prolongée qui comprend la composition (A) et la composition (B) suivantes dans un rapport de 15:85 à 50:50 en poids de nifédipine,

Composition (A): une préparation à libération rapide contenant comme ingrédient actif de la nifédipine en poudre fine cristalline ayant une dimension moyenne de particules de pas plus de 5 pm en mélange avec un support acceptable en pharmacie,

Composition (B): une préparation à libération retardée contenant comme ingrédient actif de la nifédipine en poudre fine ayant une dimension moyenne de particules de pas plus de 5 pm et ayant une couche de revêtement de surface comprenant une substance difficilement soluble dans l'eau choisie parmi l'éthylcellulose, les huiles hydrogénées et les esters de glycérine d'acides gras, et un composé entérique de haut poids moléculaire choisi parmi l'acétate-phtalate de cellulose, le phtalate d'hydroxypropylméthyl- cellulose et les copolymères acide méthacrylique-méthacrylate de méthyle dans un rapport pondéral de 1:5 à 5:1.

2. La préparation de nifédipine à libération prolongée selon la revendication 1, dans laquelle la composition (A) et la composition (B) sont mélangées dans un rapport de 20:80 à 40:60 en poids de nifédipine et la substance difficilement soluble dans l'eau et le composé entérique de haut poids moléculaire sont utilisés dans un rapport de 1:2 à 2:1 en poids.

3. La préparation de nifédipine à libération prôlongée selon la revendication 1 ou 2, dans laquelle la nifédipine en poudre fine a une dimension moyenne de particules de 1 à 4 µm.

4. La préparation de nifédipine à libération prolongée selon la revendication 1 ou 2, dans laquelle la nifédipine en poudre fine a une dimension moyenne de particules d'environ 2 um.

5. La préparation de nifédipine à libération prolongée selon la revendication 1, dans laquelle la préparation est sous la forme d'un type non compressé.

6. La préparation de nifédipine à libération prolongée selon la revendication 5, dans laquelle la forme de la préparation est une préparation en granules ou en granules fins qui est préparée en mélangeant une composition granulaire ou granulaire fine (A) et une composition granulaire ou granulaire fine (B), ou une préparation en capsules qui est préparée en conditionnant cette préparation en granules ou granules fins dans des capsules.

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